Patients with advanced incurable colorectal carcinoma who have objective measurable disease parameters will receive high dose methotrexate therapy with calcium leucovorin rescue. Its effect on inducing tumor regression and in prolonging survival of the treated group will be evaluated. Attempts will be made to correlate the total amount of drug during each infusion with the observed antitumor effect. Objective response rates in patients treated with high dose methotrexate will be correlated to performance status, nutritional status and whether or not the patient had received previous chemotherapy. The antitumor effects of methotrexate is based on its ability to inhibit its target enzyme dihydrofolate reductase. Patients who undergo tumor resection for localized disease will have tissue specimens analyzed for dihydrofolate reductase activity, the number and nature of the methotrexate binding sites, and whether or not multiple forms of enzymes exist in normal and cancerous tissues. At time of recurrence these patients will receive high dose methotrexate therapy. Correlations will then be made to determine whether or not the enzyme activity in the primary tumor would serve as a useful predictor of response to high dose methotrexate therapy.